Panobinostat/dexamethasone/SC bortezomib combo shows promise for RRMM

The combination of panobinostat, dexamethasone, and subcutaneous (SC) bortezomib shows promising responses in patients with relapsed or relapsed and refractory multiple myeloma (RRMM), according to the phase II PANORAMA 3* study. Furthermore, SC bortezomib may be preferable to the intravenous (IV) option for reducing toxicity.

“In the relapsed or RRMM setting, there is an urgent need for drugs that can overcome resistance to previous therapies and produce clinically meaningful responses in patients who progress after multiple lines of therapy,” the researchers said.

“[P]anobinostat plus bortezomib plus dexamethasone can be considered both an important later-line and earlier-line treatment option for patients with relapsed or RRMM,” they said.

This multinational, open-label study involved 248 adults (median age 66.5 years, 55 percent male) with relapsed or RRMM with ECOG performance status ≤2 who had received 1–4 previous treatments (including an immunomodulatory agent). They were randomized 1:1:1 to receive oral panobinostat 20 mg TIW, 20 mg BIW, or 10 mg TIW in addition to SC bortezomib** and oral dexamethasone (20 mg***) in 21-day cycles.

Patients had received a median two prior lines of therapy and median time since diagnosis was 49 months. They were followed up for a median 14.7 months. Patients in the 20 mg TIW, 20 mg BIW, and 10 mg TIW groups received a median nine, eight, and seven treatment cycles, respectively.

Overall response rate (ORR) after up to eight treatment cycles was higher among patients who received panobinostat 20 mg TIW or BIW compared with 10 mg TIW (62.2 and 65.1 percent vs 50.6 percent). [ASH 2020, abstract 3201; Lancet Oncol 2020;doi:10.1016/S1470-2045(20)30680-X]

Median time to response was 1, 2, and 3 months, respectively, and median duration of response (DoR) was 22, 12, and 11 months, respectively.

Acceptable safety profile

Grade ≥3 treatment-emergent adverse events (AEs) occurred in 91, 83, and 75 percent of the 20 mg TIW, 20 mg BIW, and 10 mg TIW groups, respectively. The most common were thrombocytopenia (42, 31, and 24 percent, respectively) and neutropenia (23, 16, and 8 percent, respectively). Grade ≥3 diarrhoea occurred in 12, 10, and 5 percent, respectively.

Serious AEs occurred in 54, 48, and 44 percent of panobinostat 20 mg TIW, 20 mg BIW, and 10 mg TIW recipients, respectively, the most frequent being pneumonia (12, 12, and 11 percent, respectively). Thirty, 28, and 15 percent of patients, respectively, discontinued treatment due to AEs.

Of the 14 deaths that occurred during the study (5, 3, and 6 in the 20 mg TIW, 20 mg BIW, and 10 mg TIW groups, respectively), none were considered treatment related, with 12 attributed to disease progression.

“Despite a similar ORR and number of completed cycles, the longer DoR observed with panobinostat 20 mg TIW versus 20 mg BIW suggests that increased panobinostat dosing frequency produces a longer-lasting antitumour effect against MM,” noted the researchers.

The 10 mg TIW dose, despite having a lower ORR and DoR vs the other dosing schedules, was still “active” and was the best tolerated, they added, cautioning that the study was not powered for between-group comparisons.

Results of the PANORAMA 1 trial led to the approval of oral panobinostat 20 mg TIW plus IV bortezomib and dexamethasone for relapsed or RRMM following ≥2 lines of treatment including bortezomib and an immunomodulatory agent. [Lancet Oncol 2014;15:1195-1206] However, IV bortezomib was later associated with a higher risk of peripheral neuropathy and gastrointestinal toxicity compared with the SC route.

“The safety profile of panobinostat 20 mg TIW was more favourable than in previous trials of this regimen with IV bortezomib.” This suggests that SC bortezomib may improve tolerability of the panobinostat–bortezomib–dexamethasone regimen, they pointed out.

They also noted that while AEs often warranted dose adjustments, most patients remained on treatment. “[This] suggests that toxicities could be managed with appropriate dose reductions or delays, or both.” However, efforts should be made to retain the 20 mg TIW dose if possible due to the superior ORR and DoR rates.

The researchers acknowledged study limitations including the Caucasian-majority population and the limited number of patients with prior exposure to monoclonal antibodies.